A. Anisimova, P. Rubtsov, K. A. Akulich, S. Dmitriev, E. Frolova, A. Tiulpakov
Context: Loss-of-function mutations in the POMC gene are associated with a syndrome with the characteristics of adrenal insufficiency, obesity, and red hair. We describe here a case of pro-opiomelanocortin (POMC) deficiency in which adrenal insufficiency was not treated until the fourth year of life. One of the disease-causative POMC mutations was characterized in vitro using a unique approach. Case Description: A boy presented in the first year of life with red hair, growth acceleration, moderate obesity, and recurrent cholestasis, which was followed by 2 episodes of hypoglycemia at the ages of 1.5 and 3 years. The diagnosis was suspected at the age of 3.6 years after documentation of undetectable levels of plasma adrenocorticotropic hormone and serum cortisol, after which replacement with hydrocortisone was initiated. Sequencing of the POMC gene revealed compound heterozygosity for c.-11C>A/p.W84X mutations. The p.W84X mutation is predicted to result in a marked truncation of preprohormone. Using a messenger RNA transfection approach followed by an in vitro translation assay, we could directly demonstrate that the transcript with c.-11C>A substitution is predominantly translated within a new open reading frame; however, translation of the POMC main reading frame is preserved, with translation efficiency being ∼17% of the wild-type transcript. Conclusions: The current report provides important information on the natural course of POMC deficiency. In vitro translation studies demonstrated residual translation of the main coding region from an allele with the c.-11C>A mutation, which at least partially explains a relatively late presentation of adrenal insufficiency in the patient.
{"title":"Late Diagnosis of POMC Deficiency and In Vitro Evidence of Residual Translation From Allele With c.-11C>A Mutation","authors":"A. Anisimova, P. Rubtsov, K. A. Akulich, S. Dmitriev, E. Frolova, A. Tiulpakov","doi":"10.1210/jc.2016-3318","DOIUrl":"https://doi.org/10.1210/jc.2016-3318","url":null,"abstract":"Context: Loss-of-function mutations in the POMC gene are associated with a syndrome with the characteristics of adrenal insufficiency, obesity, and red hair. We describe here a case of pro-opiomelanocortin (POMC) deficiency in which adrenal insufficiency was not treated until the fourth year of life. One of the disease-causative POMC mutations was characterized in vitro using a unique approach. Case Description: A boy presented in the first year of life with red hair, growth acceleration, moderate obesity, and recurrent cholestasis, which was followed by 2 episodes of hypoglycemia at the ages of 1.5 and 3 years. The diagnosis was suspected at the age of 3.6 years after documentation of undetectable levels of plasma adrenocorticotropic hormone and serum cortisol, after which replacement with hydrocortisone was initiated. Sequencing of the POMC gene revealed compound heterozygosity for c.-11C>A/p.W84X mutations. The p.W84X mutation is predicted to result in a marked truncation of preprohormone. Using a messenger RNA transfection approach followed by an in vitro translation assay, we could directly demonstrate that the transcript with c.-11C>A substitution is predominantly translated within a new open reading frame; however, translation of the POMC main reading frame is preserved, with translation efficiency being ∼17% of the wild-type transcript. Conclusions: The current report provides important information on the natural course of POMC deficiency. In vitro translation studies demonstrated residual translation of the main coding region from an allele with the c.-11C>A mutation, which at least partially explains a relatively late presentation of adrenal insufficiency in the patient.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"2 1","pages":"359–362"},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86939959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jieli Lu, Limin Wang, Mian Li, Yu Xu, Yong Jiang, Weiqing Wang, Jian-hong Li, S. Mi, Mei Zhang, Yichong Li, Tiange Wang, Min Xu, Zhiyun Zhao, M. Dai, S. Lai, Wenhua Zhao, Linhong Wang, Y. Bi, G. Ning
Context: In China, data on the prevalence of metabolic syndrome have been rare recently. Objective: The objective of the study was to evaluate the prevalence of metabolic syndrome and its components in 2010. Design, Setting, and Participants: The study covered all 31 provinces of mainland China and consisted of a nationally representative population sample of 98,658 Chinese adults aged ≥18 years. Of these, 97,098 participants were eligible for the data analysis reported here. Main Outcome Measures: Estimates of the prevalence of metabolic syndrome and its components were calculated. To further explore whether metabolic syndrome is associated with the 10-year coronary heart disease risk, sex-stratified logistic regression models were used. Results: The prevalence of the metabolic syndrome was 33.9% (31.0% in men and 36.8% in women), which indicates that metabolic syndrome affects approximately 454 million adults in China. More than half of total adult population was suffering from low high-density lipoprotein cholesterol (HDL-C), and nearly half of participants had high blood pressure. Abdominal obesity and low HDL-C were more prevalent in women than in men, whereas high blood pressure, high blood glucose, and high triglycerides were more common in men. Metabolic syndrome was associated with a higher 10-year coronary heart disease risk after adjustment for potential risk factors and each component of metabolic syndrome as continuous variables. Conclusion: Our results showed a high prevalence of metabolic syndrome and its components in the general adult population in mainland China. Metabolic syndrome was independently associated with a higher 10-year risk of developing coronary heart disease.
{"title":"Metabolic Syndrome Among Adults in China: The 2010 China Noncommunicable Disease Surveillance","authors":"Jieli Lu, Limin Wang, Mian Li, Yu Xu, Yong Jiang, Weiqing Wang, Jian-hong Li, S. Mi, Mei Zhang, Yichong Li, Tiange Wang, Min Xu, Zhiyun Zhao, M. Dai, S. Lai, Wenhua Zhao, Linhong Wang, Y. Bi, G. Ning","doi":"10.1210/jc.2016-2477","DOIUrl":"https://doi.org/10.1210/jc.2016-2477","url":null,"abstract":"Context: In China, data on the prevalence of metabolic syndrome have been rare recently. Objective: The objective of the study was to evaluate the prevalence of metabolic syndrome and its components in 2010. Design, Setting, and Participants: The study covered all 31 provinces of mainland China and consisted of a nationally representative population sample of 98,658 Chinese adults aged ≥18 years. Of these, 97,098 participants were eligible for the data analysis reported here. Main Outcome Measures: Estimates of the prevalence of metabolic syndrome and its components were calculated. To further explore whether metabolic syndrome is associated with the 10-year coronary heart disease risk, sex-stratified logistic regression models were used. Results: The prevalence of the metabolic syndrome was 33.9% (31.0% in men and 36.8% in women), which indicates that metabolic syndrome affects approximately 454 million adults in China. More than half of total adult population was suffering from low high-density lipoprotein cholesterol (HDL-C), and nearly half of participants had high blood pressure. Abdominal obesity and low HDL-C were more prevalent in women than in men, whereas high blood pressure, high blood glucose, and high triglycerides were more common in men. Metabolic syndrome was associated with a higher 10-year coronary heart disease risk after adjustment for potential risk factors and each component of metabolic syndrome as continuous variables. Conclusion: Our results showed a high prevalence of metabolic syndrome and its components in the general adult population in mainland China. Metabolic syndrome was independently associated with a higher 10-year risk of developing coronary heart disease.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"175 1","pages":"507–515"},"PeriodicalIF":0.0,"publicationDate":"2016-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78739169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Yoo, Y. Ha, H. Ryu, Geunwu Chang, Young-Kyun Lee, Moon-jib Yoo, K. Koo
Context and Objective: Pain-related immobility because of insufficiency fractures may result in serious complications and a high mortality rate in senile patients with preexisting comorbidities. This study aimed to evaluate the efficacy of teriparatide in patients with sacral insufficiency fractures. Design, Setting, and Participants: This retrospective, case-controlled, single center study, performed from 2009 to 2014, included 41 patients who underwent radiographs, magnetic resonance imaging, and/or bone scans to document sacral insufficiency fractures. Intervention: The intervention involved teriparatide at a once-daily subcutaneous dose of 20 &mgr;g within 2 days of hospital admission (21 patients). Twenty patients (control group) did not receive teriparatide. Main Outcome Measures: Functional outcome was assessed using a visual analog scale for pain and the time to mobilization. Pelvic anteroposterior radiographs were repeated at 0, 1, 4, 8, 12, and 16 weeks until radiographic evidence of cortical bridging at the fracture site was confirmed. Results: From the date of admission to 4 weeks, the mean visual analog scale score improved between the 2 groups. The mean time to mobilization was 1.2 ± 0.4 weeks in patients who received teriparatide treatment, compared with 2.0 ± 0.3 weeks in controls (P < 0.001). At 8 weeks, all fractures in the teriparatide treatment group and 4 fractures in the control group had healed. Conclusions: In senile patients with preexisting comorbidities who have sacral insufficiency fractures, teriparatide treatment may achieve earlier pain reduction and mobilization and reduce healing time.
{"title":"Teriparatide Treatment in Elderly Patients With Sacral Insufficiency Fracture","authors":"J. Yoo, Y. Ha, H. Ryu, Geunwu Chang, Young-Kyun Lee, Moon-jib Yoo, K. Koo","doi":"10.1210/jc.2016-3582","DOIUrl":"https://doi.org/10.1210/jc.2016-3582","url":null,"abstract":"Context and Objective: Pain-related immobility because of insufficiency fractures may result in serious complications and a high mortality rate in senile patients with preexisting comorbidities. This study aimed to evaluate the efficacy of teriparatide in patients with sacral insufficiency fractures. Design, Setting, and Participants: This retrospective, case-controlled, single center study, performed from 2009 to 2014, included 41 patients who underwent radiographs, magnetic resonance imaging, and/or bone scans to document sacral insufficiency fractures. Intervention: The intervention involved teriparatide at a once-daily subcutaneous dose of 20 &mgr;g within 2 days of hospital admission (21 patients). Twenty patients (control group) did not receive teriparatide. Main Outcome Measures: Functional outcome was assessed using a visual analog scale for pain and the time to mobilization. Pelvic anteroposterior radiographs were repeated at 0, 1, 4, 8, 12, and 16 weeks until radiographic evidence of cortical bridging at the fracture site was confirmed. Results: From the date of admission to 4 weeks, the mean visual analog scale score improved between the 2 groups. The mean time to mobilization was 1.2 ± 0.4 weeks in patients who received teriparatide treatment, compared with 2.0 ± 0.3 weeks in controls (P < 0.001). At 8 weeks, all fractures in the teriparatide treatment group and 4 fractures in the control group had healed. Conclusions: In senile patients with preexisting comorbidities who have sacral insufficiency fractures, teriparatide treatment may achieve earlier pain reduction and mobilization and reduce healing time.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"1 1","pages":"560–565"},"PeriodicalIF":0.0,"publicationDate":"2016-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89499952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. Mañé, J. F. Flores-Le Roux, D. Benaiges, Marta Rodríguez, Irene Marcelo, J. Chillarón, J. Pedro-botet, Gemma Llauradó, Lucía Gortazar, R. Carreras, A. Payà
Context Risk of obstetric complications increases linearly with rising maternal glycemia. Testing hemoglobin A1c (HbA1c) is an effective option to detect hyperglycemia, but its association with adverse pregnancy outcomes remains unclear. Emerging data sustain that an early HbA1c ≥5.9% could act as a pregnancy risk marker. Objective To determine, in a multiethnic cohort, whether an early ≥5.9% HbA1c could be useful to identify women without diabetes mellitus at increased pregnancy risk. Design and Setting A prospective study was conducted at Hospital del Mar, Barcelona, between April 2013 and September 2015. Patients and Intervention A total of 1631 pregnant women had an HbA1c measurement added to their first antenatal blood tests and were screened for gestational diabetes mellitus at 24 to 28 weeks' gestation. Outcome Measures Primary outcome was macrosomia. Secondary outcomes were preeclampsia, preterm birth, and cesarean section rate. Results A total of 1228 pregnancies were included for outcome analysis. Women with HbA1c ≥5.9% (n = 48) showed a higher rate of macrosomia (16.7% vs 5.9%, P = 0.008) and a tendency toward a higher rate of preeclampsia (9.32% vs 3.9%, P = 0.092). There were no statistically significant differences in other pregnancy outcomes. After adjusting for potential confounders, an HbA1c ≥5.9% was independently associated with a 3-fold increased risk of macrosomia (95% confidence interval, 1.127 to 8.603, P = 0.028) and preeclampsia (95% confidence interval, 1.086 to 11.532, P = 0.036). Conclusions In a multiethnic population, an early HbA1c ≥5.9% measurement identifies women at high risk for poorer pregnancy outcomes independently of gestational diabetes mellitus diagnosis later in pregnancy. Further studies are required to establish cutoff points adapted to each ethnic group and to assess whether early detection and treatment are of benefit.
产科并发症的风险随着产妇血糖升高呈线性增加。检测糖化血红蛋白(HbA1c)是检测高血糖的有效选择，但其与不良妊娠结局的关系尚不清楚。新出现的数据支持早期HbA1c≥5.9%可作为妊娠风险标志。目的在一项多民族队列研究中，确定早期HbA1c≥5.9%是否有助于识别无糖尿病的妊娠风险增加的女性。设计与环境一项前瞻性研究于2013年4月至2015年9月在巴塞罗那del Mar医院进行。患者和干预总共有1631名孕妇在第一次产前血液检查中增加了HbA1c测量，并在妊娠24至28周筛查妊娠糖尿病。主要结局为巨大儿。次要结局为先兆子痫、早产和剖宫产率。结果共纳入1228例妊娠进行结局分析。HbA1c≥5.9%的女性(n = 48)显示出较高的巨大儿发生率(16.7% vs 5.9%， P = 0.008)和较高的先兆子痫发生率(9.32% vs 3.9%， P = 0.092)。在其他妊娠结局方面没有统计学上的显著差异。在调整潜在混杂因素后，HbA1c≥5.9%与巨大儿(95%置信区间，1.127 ~ 8.603,P = 0.028)和先兆子痫(95%置信区间，1.086 ~ 11.532,P = 0.036)风险增加3倍独立相关。结论:在多民族人群中，早期HbA1c≥5.9%的检测可识别出妊娠结局较差的高危女性，与妊娠后期诊断妊娠糖尿病无关。需要进一步的研究来确定适合每个种族群体的临界值，并评估早期发现和治疗是否有益。
{"title":"Role of First-Trimester HbA1c as a Predictor of Adverse Obstetric Outcomes in a Multiethnic Cohort","authors":"L. Mañé, J. F. Flores-Le Roux, D. Benaiges, Marta Rodríguez, Irene Marcelo, J. Chillarón, J. Pedro-botet, Gemma Llauradó, Lucía Gortazar, R. Carreras, A. Payà","doi":"10.1210/jc.2016-2581","DOIUrl":"https://doi.org/10.1210/jc.2016-2581","url":null,"abstract":"Context\u0000Risk of obstetric complications increases linearly with rising maternal glycemia. Testing hemoglobin A1c (HbA1c) is an effective option to detect hyperglycemia, but its association with adverse pregnancy outcomes remains unclear. Emerging data sustain that an early HbA1c ≥5.9% could act as a pregnancy risk marker.\u0000\u0000\u0000Objective\u0000To determine, in a multiethnic cohort, whether an early ≥5.9% HbA1c could be useful to identify women without diabetes mellitus at increased pregnancy risk.\u0000\u0000\u0000Design and Setting\u0000A prospective study was conducted at Hospital del Mar, Barcelona, between April 2013 and September 2015.\u0000\u0000\u0000Patients and Intervention\u0000A total of 1631 pregnant women had an HbA1c measurement added to their first antenatal blood tests and were screened for gestational diabetes mellitus at 24 to 28 weeks' gestation.\u0000\u0000\u0000Outcome Measures\u0000Primary outcome was macrosomia. Secondary outcomes were preeclampsia, preterm birth, and cesarean section rate.\u0000\u0000\u0000Results\u0000A total of 1228 pregnancies were included for outcome analysis. Women with HbA1c ≥5.9% (n = 48) showed a higher rate of macrosomia (16.7% vs 5.9%, P = 0.008) and a tendency toward a higher rate of preeclampsia (9.32% vs 3.9%, P = 0.092). There were no statistically significant differences in other pregnancy outcomes. After adjusting for potential confounders, an HbA1c ≥5.9% was independently associated with a 3-fold increased risk of macrosomia (95% confidence interval, 1.127 to 8.603, P = 0.028) and preeclampsia (95% confidence interval, 1.086 to 11.532, P = 0.036).\u0000\u0000\u0000Conclusions\u0000In a multiethnic population, an early HbA1c ≥5.9% measurement identifies women at high risk for poorer pregnancy outcomes independently of gestational diabetes mellitus diagnosis later in pregnancy. Further studies are required to establish cutoff points adapted to each ethnic group and to assess whether early detection and treatment are of benefit.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"14 1","pages":"390–397"},"PeriodicalIF":0.0,"publicationDate":"2016-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86168644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Wallia, K. Schmidt, Diana Johnson Oakes, Teresa Pollack, N. Welsh, S. Kling-Colson, Suruchi Gupta, Candice Fulkerson, G. Aleppo, N. Parikh, J. Levitsky, JP Norvell, A. Rademaker, M. Molitch
Context: Previous studies have shown a relationship between glycemic control and posttransplant morbidity. Objective: We conducted a prospective randomized controlled trial in postliver transplant patients to evaluate intensive inpatient glycemic control and effects on outcomes to 1 year. Research Design and Intervention: A total of 164 patients [blood glucose (BG) >180 mg/dL] were randomized into 2 target groups: 82 with a BG of 140 mg/dL and 82 with a BG of 180 mg/dL. Continuous insulin infusions were initiated and then converted to subcutaneous basal bolus insulin therapy by our glucose management service. Results: The inpatient mean BG level was significantly different (140 group, 151.4 ± 19.5 mg/dL vs 180 group, 172.6 ± 27.9 mg/dL; P < 0.001). Any infection within 1 year occurred in 35 of the 82 patients (42.7%) in the 140 group and 54 of 82 (65.9%) in the 180 group (P = 0.0046). In a time-to-first infection analysis, being in the 140 group resulted in a hazard ratio of 0.54 (95% confidence interval, 0.35 to 0.83; P = 0.004); the difference between the 2 groups was statistically significant at 1 month (P = 0.008). The number with adjudicated transplant rejection was similar between the 2 groups [17 of 82 (20.7%) and 20 of 82 (24.3%) in the 140 and 180 groups, respectively; P = not significant]. Severe hypoglycemia (BG ⩽40 mg/dL) occurred in 3 patients (2 in the 140 group and 1 in the 180 group). However, more patients had moderate hypoglycemia (BG, 41 to 70 mg/dL) in the 140 group [27 of 82 (32.9%) vs 10 of 82 (12.2%) in the 180 group; P = 0.003]. Insulin-related hypoglycemia was not associated with the incidence of severe adverse outcomes. Conclusions: Glycemic control of 140 mg/dL safely resulted in a reduced incidence of infection after transplantation compared with 180 mg/dL, but with an increase in moderate hypoglycemia.
{"title":"Glycemic Control Reduces Infections in Post–Liver Transplant Patients: Results of a Prospective, Randomized Study","authors":"A. Wallia, K. Schmidt, Diana Johnson Oakes, Teresa Pollack, N. Welsh, S. Kling-Colson, Suruchi Gupta, Candice Fulkerson, G. Aleppo, N. Parikh, J. Levitsky, JP Norvell, A. Rademaker, M. Molitch","doi":"10.1210/jc.2016-3279","DOIUrl":"https://doi.org/10.1210/jc.2016-3279","url":null,"abstract":"Context: Previous studies have shown a relationship between glycemic control and posttransplant morbidity. Objective: We conducted a prospective randomized controlled trial in postliver transplant patients to evaluate intensive inpatient glycemic control and effects on outcomes to 1 year. Research Design and Intervention: A total of 164 patients [blood glucose (BG) >180 mg/dL] were randomized into 2 target groups: 82 with a BG of 140 mg/dL and 82 with a BG of 180 mg/dL. Continuous insulin infusions were initiated and then converted to subcutaneous basal bolus insulin therapy by our glucose management service. Results: The inpatient mean BG level was significantly different (140 group, 151.4 ± 19.5 mg/dL vs 180 group, 172.6 ± 27.9 mg/dL; P < 0.001). Any infection within 1 year occurred in 35 of the 82 patients (42.7%) in the 140 group and 54 of 82 (65.9%) in the 180 group (P = 0.0046). In a time-to-first infection analysis, being in the 140 group resulted in a hazard ratio of 0.54 (95% confidence interval, 0.35 to 0.83; P = 0.004); the difference between the 2 groups was statistically significant at 1 month (P = 0.008). The number with adjudicated transplant rejection was similar between the 2 groups [17 of 82 (20.7%) and 20 of 82 (24.3%) in the 140 and 180 groups, respectively; P = not significant]. Severe hypoglycemia (BG ⩽40 mg/dL) occurred in 3 patients (2 in the 140 group and 1 in the 180 group). However, more patients had moderate hypoglycemia (BG, 41 to 70 mg/dL) in the 140 group [27 of 82 (32.9%) vs 10 of 82 (12.2%) in the 180 group; P = 0.003]. Insulin-related hypoglycemia was not associated with the incidence of severe adverse outcomes. Conclusions: Glycemic control of 140 mg/dL safely resulted in a reduced incidence of infection after transplantation compared with 180 mg/dL, but with an increase in moderate hypoglycemia.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"39 1","pages":"451–459"},"PeriodicalIF":0.0,"publicationDate":"2016-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79046813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Ohlsson, D. Sundh, Andreas Wallerek, M. Nilsson, M. Karlsson, H. Johansson, D. Mellström, M. Lorentzon
Context: Areal bone mineral density (aBMD) measured using dual-energy X-ray absorptiometry (DXA) is used clinically to predict fracture but does not discriminate between trabecular and cortical bone assessment. Objective: This study aimed to investigate whether information on cortical and trabecular bone predict fracture risk independently of aBMD and clinical risk factors. Design and Participants: Cortical area, bone mass, porosity, and trabecular bone volume fraction (BVTV) were measured at the tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT) in 456 men (80.2 ± 3.5 years) recruited from the general population in Gothenburg, Sweden. aBMD was measured using DXA. Incident fractures (71 men) were X-ray verified. Associations were evaluated using Cox regression. Results: Cortical area [hazard ratio (HR) per standard deviation (SD) decrease, 2.05; 95% confidence interval (CI), 1.58 to 2.65], cortical bone mass (HR, 2.07; 95% CI, 1.58 to 2.70), and BVTV (HR, 1.62; 95% CI, 1.26 to 2.07), but not cortical porosity, were independently associated with fracture risk. These associations remained after adjustment for femoral neck aBMD and Fracture Risk Assessment risk factors (area: HR 1.96, 95% CI, 1.44 to 2.66; mass: HR 1.99, 95% CI, 1.45 to 2.74; BV/TV: HR 1.46, 95% CI, 1.09 to 1.96). After entering BV/TV and cortical area or bone mass simultaneously in the adjusted models, only the cortical parameters remained important predictors of fracture. Conclusion: HR-pQCT measurement of cortical area and mass might add clinically useful information for the evaluation of fracture risk.
{"title":"Cortical Bone Area Predicts Incident Fractures Independently of Areal Bone Mineral Density in Older Men","authors":"C. Ohlsson, D. Sundh, Andreas Wallerek, M. Nilsson, M. Karlsson, H. Johansson, D. Mellström, M. Lorentzon","doi":"10.1210/jc.2016-3177","DOIUrl":"https://doi.org/10.1210/jc.2016-3177","url":null,"abstract":"Context: Areal bone mineral density (aBMD) measured using dual-energy X-ray absorptiometry (DXA) is used clinically to predict fracture but does not discriminate between trabecular and cortical bone assessment. Objective: This study aimed to investigate whether information on cortical and trabecular bone predict fracture risk independently of aBMD and clinical risk factors. Design and Participants: Cortical area, bone mass, porosity, and trabecular bone volume fraction (BVTV) were measured at the tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT) in 456 men (80.2 ± 3.5 years) recruited from the general population in Gothenburg, Sweden. aBMD was measured using DXA. Incident fractures (71 men) were X-ray verified. Associations were evaluated using Cox regression. Results: Cortical area [hazard ratio (HR) per standard deviation (SD) decrease, 2.05; 95% confidence interval (CI), 1.58 to 2.65], cortical bone mass (HR, 2.07; 95% CI, 1.58 to 2.70), and BVTV (HR, 1.62; 95% CI, 1.26 to 2.07), but not cortical porosity, were independently associated with fracture risk. These associations remained after adjustment for femoral neck aBMD and Fracture Risk Assessment risk factors (area: HR 1.96, 95% CI, 1.44 to 2.66; mass: HR 1.99, 95% CI, 1.45 to 2.74; BV/TV: HR 1.46, 95% CI, 1.09 to 1.96). After entering BV/TV and cortical area or bone mass simultaneously in the adjusted models, only the cortical parameters remained important predictors of fracture. Conclusion: HR-pQCT measurement of cortical area and mass might add clinically useful information for the evaluation of fracture risk.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"51 1","pages":"516–524"},"PeriodicalIF":0.0,"publicationDate":"2016-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82672194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T. Schneider, D. de Wit, T. Links, N. V. van Erp, J. J. M. van der Hoeven, H. Gelderblom, I. Roozen, M. Bos, W. Corver, T. van Wezel, J. Smit, H. Morreau, H. Guchelaar, E. Kapiteijn
Background Mammalian target of rapamycin (mTOR) upregulation has been reported to be involved in the pathogenesis of thyroid tumors, and treatment with the mTOR inhibitor everolimus has shown promising results in endocrine tumors. We conducted a prospective phase II clinical trial to determine the efficacy and safety of everolimus in patients with advanced follicular-derived thyroid cancer. Patients and Methods Twenty-eight patients with progressive metastatic or locally advanced radioactive refractory differentiated thyroid cancer and 7 patients with anaplastic thyroid cancer were included and received everolimus 10 mg orally once daily. The primary endpoint was disease control rate [complete (CR) + partial response (PR) + stable disease (SD) > 24 weeks]. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and mutational and pharmacokinetic-related outcomes. Results Median follow-up duration was 38 months (2-64). Seventeen patients (65%) showed SD, of which 15 (58%) showed SD >24 weeks. No CR or PR was observed. Median PFS and OS were 9 [95% confidence interval (CI): 4 to 14] and 18 (95% CI: 7 to 29) months, respectively. Survival was negatively influenced by the presence of bone metastases. Toxicity was predominantly grade 1/2 and included anemia (64%), cough (64%), stomatitis (61%), and hyperglycemia (61%). Duration of SD was related to everolimus exposure. The presence of somatic gene variants related to mTOR signaling did not clearly stratify for responses. Conclusion Everolimus has clinically relevant antitumor activity in patients with advanced differentiated thyroid cancer. Given the observed disease control rate and the relatively low toxicity profile, further investigation of everolimus in sequential or combination therapy in these patients is warranted.
{"title":"Everolimus in Patients With Advanced Follicular-Derived Thyroid Cancer: Results of a Phase II Clinical Trial","authors":"T. Schneider, D. de Wit, T. Links, N. V. van Erp, J. J. M. van der Hoeven, H. Gelderblom, I. Roozen, M. Bos, W. Corver, T. van Wezel, J. Smit, H. Morreau, H. Guchelaar, E. Kapiteijn","doi":"10.1210/jc.2016-2525","DOIUrl":"https://doi.org/10.1210/jc.2016-2525","url":null,"abstract":"Background\u0000Mammalian target of rapamycin (mTOR) upregulation has been reported to be involved in the pathogenesis of thyroid tumors, and treatment with the mTOR inhibitor everolimus has shown promising results in endocrine tumors. We conducted a prospective phase II clinical trial to determine the efficacy and safety of everolimus in patients with advanced follicular-derived thyroid cancer.\u0000\u0000\u0000Patients and Methods\u0000Twenty-eight patients with progressive metastatic or locally advanced radioactive refractory differentiated thyroid cancer and 7 patients with anaplastic thyroid cancer were included and received everolimus 10 mg orally once daily. The primary endpoint was disease control rate [complete (CR) + partial response (PR) + stable disease (SD) > 24 weeks]. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and mutational and pharmacokinetic-related outcomes.\u0000\u0000\u0000Results\u0000Median follow-up duration was 38 months (2-64). Seventeen patients (65%) showed SD, of which 15 (58%) showed SD >24 weeks. No CR or PR was observed. Median PFS and OS were 9 [95% confidence interval (CI): 4 to 14] and 18 (95% CI: 7 to 29) months, respectively. Survival was negatively influenced by the presence of bone metastases. Toxicity was predominantly grade 1/2 and included anemia (64%), cough (64%), stomatitis (61%), and hyperglycemia (61%). Duration of SD was related to everolimus exposure. The presence of somatic gene variants related to mTOR signaling did not clearly stratify for responses.\u0000\u0000\u0000Conclusion\u0000Everolimus has clinically relevant antitumor activity in patients with advanced differentiated thyroid cancer. Given the observed disease control rate and the relatively low toxicity profile, further investigation of everolimus in sequential or combination therapy in these patients is warranted.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"30 1","pages":"698–707"},"PeriodicalIF":0.0,"publicationDate":"2016-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85365100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frida Dalin, Gabriel Nordling Eriksson, P. Dahlqvist, Å. Hallgren, J. Wahlberg, O. Ekwall, S. Söderberg, J. Rönnelid, P. Olcén, O. Winqvist, S. Catrina, B. Kriström, Maria Laudius, M. Isaksson, Maria Halldin Stenlid, J. Gustafsson, G. Gebre-Medhin, S. Björnsdóttir, A. Janson, A. Åkerman, J. Åman, K. Duchén, Ragnhildur Bergthorsdottir, G. Johannsson, E. Lindskog, M. Landin-Olsson, M. Elfving, E. Waldenström, A. Hulting, O. Kämpe, S. Bensing
Context: Studies of the clinical and immunological features of autoimmune Addison disease (AAD) are needed to understand the disease burden and increased mortality. Objective: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles, and cardiovascular risk factors. Design, Setting, and Participants: A cross-sectional, population-based study that included 660 AAD patients from the Swedish Addison Registry (2008–2014). When analyzing the cardiovascular risk factors, 3594 individuals from the population-based survey in Northern Sweden, MONICA (monitoring of trends and determinants of cardiovascular disease), served as controls. Main Outcome Measures: The endpoints were the prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined. Results: The proportion of 21-hydroxylase autoantibody-positive patients was 83%, and 62% of patients had ≥1 associated autoimmune diseases, more frequently coexisting in females (P < 0.0001). AAD patients had a lower body mass index (P < 0.0001) and prevalence of hypertension (P = 0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of the patients, with a mean dose of 28.1 ± 8.5 mg/d. The mean hydrocortisone equivalent dose normalized to the body surface was 14.8 ± 4.4 mg/m2/d. A greater hydrocortisone equivalent dose was associated with a greater incidence of hypertension (P = 0.046). Conclusions: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients did not have an increased prevalence of overweight, hypertension, type 2 diabetes mellitus, or hyperlipidemia. However, high glucocorticoid replacement doses could be a risk factor for hypertension.
{"title":"Clinical and Immunological Characteristics of Autoimmune Addison Disease: A Nationwide Swedish Multicenter Study","authors":"Frida Dalin, Gabriel Nordling Eriksson, P. Dahlqvist, Å. Hallgren, J. Wahlberg, O. Ekwall, S. Söderberg, J. Rönnelid, P. Olcén, O. Winqvist, S. Catrina, B. Kriström, Maria Laudius, M. Isaksson, Maria Halldin Stenlid, J. Gustafsson, G. Gebre-Medhin, S. Björnsdóttir, A. Janson, A. Åkerman, J. Åman, K. Duchén, Ragnhildur Bergthorsdottir, G. Johannsson, E. Lindskog, M. Landin-Olsson, M. Elfving, E. Waldenström, A. Hulting, O. Kämpe, S. Bensing","doi":"10.1210/jc.2016-2522","DOIUrl":"https://doi.org/10.1210/jc.2016-2522","url":null,"abstract":"Context: Studies of the clinical and immunological features of autoimmune Addison disease (AAD) are needed to understand the disease burden and increased mortality. Objective: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles, and cardiovascular risk factors. Design, Setting, and Participants: A cross-sectional, population-based study that included 660 AAD patients from the Swedish Addison Registry (2008–2014). When analyzing the cardiovascular risk factors, 3594 individuals from the population-based survey in Northern Sweden, MONICA (monitoring of trends and determinants of cardiovascular disease), served as controls. Main Outcome Measures: The endpoints were the prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined. Results: The proportion of 21-hydroxylase autoantibody-positive patients was 83%, and 62% of patients had ≥1 associated autoimmune diseases, more frequently coexisting in females (P < 0.0001). AAD patients had a lower body mass index (P < 0.0001) and prevalence of hypertension (P = 0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of the patients, with a mean dose of 28.1 ± 8.5 mg/d. The mean hydrocortisone equivalent dose normalized to the body surface was 14.8 ± 4.4 mg/m2/d. A greater hydrocortisone equivalent dose was associated with a greater incidence of hypertension (P = 0.046). Conclusions: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients did not have an increased prevalence of overweight, hypertension, type 2 diabetes mellitus, or hyperlipidemia. However, high glucocorticoid replacement doses could be a risk factor for hypertension.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"314 1","pages":"379–389"},"PeriodicalIF":0.0,"publicationDate":"2016-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80062375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
V. Marotta, Concetta Sciammarella, M. Capasso, A. Testori, C. Pivonello, M. G. Chiofalo, C. Gambardella, M. Grasso, A. Antonino, A. Annunziata, P. Macchia, R. Pivonello, L. Santini, G. Botti, S. Losito, L. Pezzullo, A. Colao, A. Faggiano
Context: Tumor angiogenesis is determined by host genetic background rather than environment. Germline single nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) pathway have demonstrated prognostic value in different tumors. Objectives: Our main objective was to test the prognostic value of germline SNPs of the VEGF pathway in nonadvanced differentiated thyroid cancer (DTC). Secondarily, we sought to correlate analyzed SNPs with microvessel density (MVD). Design: Multicenter, retrospective, observational study. Setting: Four referral centers. Patients: Blood samples were obtained from consecutive DTC patients. Genotyping was performed according to the TaqMan protocol, including 4 VEGF-A (−2578C>A, −460T>C, +405G>C, and +936C>T) and 2 VEGFR-2 (+1192 C>T and +1719 T>A) SNPs. MVD was estimated by means of CD34 staining. Outcome Measures: Rate of recurrent structural disease/disease-free survival (DFS). Difference in MVD between tumors from patients with different genotype. Results: Two hundred four patients with stage I–II DTC (mean follow-up, 73 ± 64 months) and 240 patients with low- to intermediate-risk DTC (mean follow-up, 70 ± 60 months) were enrolled. Two “risk” genotypes were identified by combining VEGF-A SNPs −2578 C>A, −460 T>C, and +405 G>C. The ACG homozygous genotype was protective in both stage I–II (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.01 to 1.43; P = 0.018) and low- to intermediate-risk (OR, 0.14; 95% CI, 0.01 to 1.13; P = 0.035) patients. The CTG homozygous genotype was significantly associated with recurrence in stage I–II (OR, 5.47; 95% CI, 1.15 to 26.04; P = 0.018) and was slightly deleterious in low- to intermediate-risk (OR, 3.39; 95% CI, 0.8 to 14.33; P = 0.079) patients. MVD of primary tumors from patients harboring a protective genotype was significantly lower (median MVD, 76.5 ± 12.7 and 86.7 ± 27.9, respectively; P = 0.024). Conclusions: Analysis of germline VEGF-A SNPs could empower a prognostic approach to DTC.
{"title":"Germline Polymorphisms of the VEGF Pathway Predict Recurrence in Nonadvanced Differentiated Thyroid Cancer","authors":"V. Marotta, Concetta Sciammarella, M. Capasso, A. Testori, C. Pivonello, M. G. Chiofalo, C. Gambardella, M. Grasso, A. Antonino, A. Annunziata, P. Macchia, R. Pivonello, L. Santini, G. Botti, S. Losito, L. Pezzullo, A. Colao, A. Faggiano","doi":"10.1210/jc.2016-2555","DOIUrl":"https://doi.org/10.1210/jc.2016-2555","url":null,"abstract":"Context: Tumor angiogenesis is determined by host genetic background rather than environment. Germline single nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) pathway have demonstrated prognostic value in different tumors. Objectives: Our main objective was to test the prognostic value of germline SNPs of the VEGF pathway in nonadvanced differentiated thyroid cancer (DTC). Secondarily, we sought to correlate analyzed SNPs with microvessel density (MVD). Design: Multicenter, retrospective, observational study. Setting: Four referral centers. Patients: Blood samples were obtained from consecutive DTC patients. Genotyping was performed according to the TaqMan protocol, including 4 VEGF-A (−2578C>A, −460T>C, +405G>C, and +936C>T) and 2 VEGFR-2 (+1192 C>T and +1719 T>A) SNPs. MVD was estimated by means of CD34 staining. Outcome Measures: Rate of recurrent structural disease/disease-free survival (DFS). Difference in MVD between tumors from patients with different genotype. Results: Two hundred four patients with stage I–II DTC (mean follow-up, 73 ± 64 months) and 240 patients with low- to intermediate-risk DTC (mean follow-up, 70 ± 60 months) were enrolled. Two “risk” genotypes were identified by combining VEGF-A SNPs −2578 C>A, −460 T>C, and +405 G>C. The ACG homozygous genotype was protective in both stage I–II (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.01 to 1.43; P = 0.018) and low- to intermediate-risk (OR, 0.14; 95% CI, 0.01 to 1.13; P = 0.035) patients. The CTG homozygous genotype was significantly associated with recurrence in stage I–II (OR, 5.47; 95% CI, 1.15 to 26.04; P = 0.018) and was slightly deleterious in low- to intermediate-risk (OR, 3.39; 95% CI, 0.8 to 14.33; P = 0.079) patients. MVD of primary tumors from patients harboring a protective genotype was significantly lower (median MVD, 76.5 ± 12.7 and 86.7 ± 27.9, respectively; P = 0.024). Conclusions: Analysis of germline VEGF-A SNPs could empower a prognostic approach to DTC.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"8 1","pages":"661–671"},"PeriodicalIF":0.0,"publicationDate":"2016-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78909564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
David Reyes-Umpierrez, Georgia M Davis, Saumeth Cardona, F. Pasquel, Limin Peng, S. Jacobs, P. Vellanki, M. Fayfman, Sonya Haw, Michael E. Halkos, R. Guyton, V. Thourani, G. Umpierrez
Objective We aimed to determine (a) longitudinal changes of inflammatory and oxidative stress markers and (b) the association between markers of inflammation and perioperative complications in coronary artery bypass surgery (CABG) patients treated with intensive vs conservative blood glucose (BG) control. Methods Patients with diabetes (n = 152) and without diabetes with hyperglycemia (n = 150) were randomized to intensive (n = 151; BG: 100-140 mg/dL) or to conservative (n = 151; BG: 141-180 mg/dL) glycemic targets. Plasma cortisol, high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-α, interleukin-6 (IL-6), thiobarbituric acid-reactive substances, and 2'-7'-dichlorofluorescein were measured prior to and at days 3, 5, and 30 after surgery. Results Intensive glycemic control resulted in lower mean BG (132 ± 14 mg/dL vs 154 ± 17 mg/dL, P < 0.001) in the intensive care unit. Plasma cortisol and inflammatory markers increased significantly from baseline after the third and fifth day of surgery (P < 0.001), and returned to baseline levels at 1 month of follow-up. Patients with perioperative complications had higher levels of cortisol, hsCRP, IL-6, and oxidative stress markers compared with those without complications. There were no significant differences in inflammatory and oxidative stress markers between patients, with or without diabetes or complications, treated with intensive or conventional glucose targets. Conclusion We report no significant differences in circulating markers of acute inflammatory and oxidative stress response in cardiac surgery patients, with or without diabetes, treated with intensive (100-140 mg/dL) or conservative (141-180 mg/dL) insulin regimens.
{"title":"Inflammation and Oxidative Stress in Cardiac Surgery Patients Treated to Intensive Versus Conservative Glucose Targets","authors":"David Reyes-Umpierrez, Georgia M Davis, Saumeth Cardona, F. Pasquel, Limin Peng, S. Jacobs, P. Vellanki, M. Fayfman, Sonya Haw, Michael E. Halkos, R. Guyton, V. Thourani, G. Umpierrez","doi":"10.1210/jc.2016-3197","DOIUrl":"https://doi.org/10.1210/jc.2016-3197","url":null,"abstract":"Objective\u0000We aimed to determine (a) longitudinal changes of inflammatory and oxidative stress markers and (b) the association between markers of inflammation and perioperative complications in coronary artery bypass surgery (CABG) patients treated with intensive vs conservative blood glucose (BG) control.\u0000\u0000\u0000Methods\u0000Patients with diabetes (n = 152) and without diabetes with hyperglycemia (n = 150) were randomized to intensive (n = 151; BG: 100-140 mg/dL) or to conservative (n = 151; BG: 141-180 mg/dL) glycemic targets. Plasma cortisol, high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-α, interleukin-6 (IL-6), thiobarbituric acid-reactive substances, and 2'-7'-dichlorofluorescein were measured prior to and at days 3, 5, and 30 after surgery.\u0000\u0000\u0000Results\u0000Intensive glycemic control resulted in lower mean BG (132 ± 14 mg/dL vs 154 ± 17 mg/dL, P < 0.001) in the intensive care unit. Plasma cortisol and inflammatory markers increased significantly from baseline after the third and fifth day of surgery (P < 0.001), and returned to baseline levels at 1 month of follow-up. Patients with perioperative complications had higher levels of cortisol, hsCRP, IL-6, and oxidative stress markers compared with those without complications. There were no significant differences in inflammatory and oxidative stress markers between patients, with or without diabetes or complications, treated with intensive or conventional glucose targets.\u0000\u0000\u0000Conclusion\u0000We report no significant differences in circulating markers of acute inflammatory and oxidative stress response in cardiac surgery patients, with or without diabetes, treated with intensive (100-140 mg/dL) or conservative (141-180 mg/dL) insulin regimens.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"115 1","pages":"309–315"},"PeriodicalIF":0.0,"publicationDate":"2016-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80627525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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